Director's Report to the National Advisory Council on Drug Abuse

February 1997

Research Findings

Clinical and Services Research

Cigarette Smoking and Brain Monoamine Oxidase A Inhibition Dr.
Joanna Fowler and colleagues at the Brookhaven National Laboratory compared
brain monoamine oxidase A (MAO A) in nonsmokers and in smokers with [11C]clorgyline
and positron emission tomography. Results revealed that tobacco smoke exposure
was associated with a significant reduction in brain MAO A. These findings
are similar to results obtained by this group showing a reduction of brain
MAO B in smokers. Because MAO A inhibitors are effective antidepressants,
the authors suggest that MAO A inhibition should be considered as a potential
contributing factor in the high rate of smoking in depression as well as
in the development of more effective strategies for smoking cessation. Fowler,
J.S., Volkow, N.D., Wang, G.-J., Pappas, N., Logan, J., Shea, C., Alexoff,
D., MacGregor, R. R., Schyler, D.J., Zezulkova, I., & Wolf, A.P. Brain
Monoamine Oxidase A Inhibition in Cigarette Smokers. Proc. Natl. Acad. Sci.,
93, pp. 14065-14069, 1996.

Smoking Increases Dose-Dependent [3H]-Nicotine Binding in Human Postmortem
Brain
Dr. Sherry Leonard has demonstrated in human postmortem brain a significant
increase in [3H]-nicotine binding in subjects who had life-long smoking
histories until death. However, binding in life-time smokers who had quit
at least two months prior to death did not differ from subjects who never
smoked. Increased binding was observed in both hippocampus and thalamus
and due to an increase in receptor number (Bmax), with no change in receptor
affinity (Kd). Furthermore, among those who had life-long smoking histories,
the number of binding sites was correlated with degree of smoking, as measured
by average number of packs per day. Similar dose-dependent increases in
brain nicotinic receptor numbers have been reported in rodents; this is
the first reported in humans. The results suggest that increases in nicotinic
receptor levels in the human brain may underlie nicotine tolerance and addiction
in smokers. Breese, C.R., Marks, M.J., Logel, J., Adams, C.E., Sullivan,
B. Collins, A.C., & Leonard, S. Effect of Smoking History on [3H]-Nicotine
Binding in Human Postmortem Brain. J Pharm Exp Ther, In Press.
Linkage of 7-nicotinic Receptor to a Neurophysiological Deficit in Schizophrenia
Using a genome-wide linkage analysis, an auditory suppression deficit seen
in most schizophrenic patients and many of their (non-schizophrenic) relatives,
was linked to a dinucleotide polymorphism at chromosome 15q14, the site
of the 7-nicotinic receptor. The deficit has to do with an abnormal suppression
or gating of the evoked response to the second of paired auditory stimuli.
This is one of several physiological markers that are associated with schizophrenic
diagnosis. In rodents the deficit is normalized by selective stimulation
of the 7-nicotinic receptor; high doses of nicotine in schizophrenics demonstrates
similar normalization. Smoking is highly prevalent in schizophrenic patients,
and it has been hypothesized that they may be self-medicating a neurophysiological
deficit. These data support this notion, demonstrating a genetic link. Freedman,
R., Coon, H., Mules-Worsley, M., Orr-Urtreger, A., Olincy, A., Davis, A.,
Polymeropoulos, M., Holik, J., Hopkins, J., Hoff, M., Rosenthal, J., Waldo,
M.C., Reimherr, F., Wender, P., Yaw, J.,Young, D.A., Breese, C.R., Adams,
C., Patterson, D., Adler, L.E., Kruglyak, L., Leonard, S., & Byerley,
W. Linkage of a Neurophysiological Deficit in Schizophrenia to a Chromosome
15 Locus. Proceedings of the National Academy of Science, January 21, 1997.

Smoking Has a Differential Effect on Cognitive Performance and Electrophysiological
Measures Depending on Task Difficulty Post-smoking response times improved
(decreased) for simple "oddball" tasks, both auditory and visual,
but only in smokers whose breath carbon monoxide levels did not change substantially
after smoking. This was accompanied by an increase in P300 amplitudes in
the visual condition only. However, smokers as a group (i.e., pooled for
carbon monoxide changes) did not significantly differ in performance before
and after smoking. By contrast, post-smoking response times worsened for
a memory task for memory sets of 6 items. There was a concomitant decrease
in P300 amplitudes and latency. These results suggest that cigarette smoking
may have enhancing effects for simple tasks, but is detrimental to more
complex tasks reflected both in cognitive performance and electrophysiological
responses. Ilan, A.B., & Polich, J. The Effects of Smoking on ERPs in
Simple and Demanding Tasks. Psychophysiology, 33, S47 (presented at the
meetings of the Society for Psychophysiological Research, Vancouver, B.C.,
Canada), 1996.

LSD Effects on Brain Dr. Henry David Abraham of the Butler Hospital
in Providence, RI recently published an article entitled "LSD-Like
Panic from Risperidone in Post-LSD Visual Disorder" in the Journal
of Clinical Psychopharmacology. Dr. Abraham found that there was an unanticipated
worsening of visual symptoms and induction of panic anxiety in patients,
who had taken LSD 4-20 years ago, given risperidone, an antagonist of the
serotonin-2 receptor. The exacerbation of visual disturbances and flashback-like
experiences suggests that LSD could act as an excitotoxin at serotonin-2
receptor, cause dysfunction of inhibitory cortical interneurons and result
in disinhibition of visual processors.

Neuropsychological Functioning in Cocaine Abuse NIDA-funded researcher
Dr. Tony L. Strickland, Ph.D., of Charles R. Drew University of Medicine
& Science and the University of California at Los Angeles (UCLA) School
of Medicine, presented preliminary findings from his ongoing NIDA-funded
research study on neurobehavioral functioning among cocaine abusers at the
National Academy of Neuropsychology Sixteenth Annual Meeting on November
1, 1996. The focus of this paper was on neuropsychological effects of chronic
cocaine use following sustained abstinence. Subjects included 37 males and
34 female freebase cocaine abusers with verifiable abstinence of between
5 and 18 months. The sample was 72% African-American and 28% Euro-American
with similar representation by gender. Statistical analyses revealed significant
impairment on measures of attention-concentration, memory, academic achievement,
with visuospatial, motor, language and executive functioning measures less
consistently impaired. Interestingly, despite a substantial gender disparity
in cocaine exposure, women appeared no more impaired on neuropsychological
measures than men. Curiously, greater cocaine exposure did not appear to
result in greater neuropsychological impairment. An abstract of the paper
will be published in the journal Archives of Clinical Neuropsychology.

Beneficial Effects of Thiamine on Recognition Memory and P300 in Abstinent
Cocaine Dependent Patients Researchers evaluated the effects of thiamine
versus placebo on memory task performance and event-related electroencephalographic
potentials in 8 abstinent cocaine dependent patients. Patients orally ingested
5 g of thiamine and 5 g of a lactose placebo on two separate days scheduled
approximately one week apart. The order of administration was randomized.
Double blind procedures were followed. Approximately three hours after ingesting
the capsules, patients completed Stemberg's (1975) memory scanning task
during which performance and event-related potentials (P300) were recorded
simultaneously. Thiamine was found to significantly improve recognition
accuracy and P300 amplitude, at the midline parietal (Pz) electrode. The
improvement was most reliable under conditions of increased memory load.
These preliminary findings justify a further examination of the relationship
between thiamine's hypothesized effects on central nervous system cholinergic
function, and the direct and indirect effects of cocaine alone. Eston, C.
and Bauer, L. Psychiatry Research, In Press.

The Effects of Anabolic Steroids on Driving Performance as Assessed by
the Iowa Driver Simulator Perry and his colleagues at the University
of Iowa studied the effects of physiologic (100 mg/wk) and supraphysiologic
(250 and 500 mg/wk) doses of testosterone cypionate (TC) on automobile driving
using the Iowa Driver Simulator. Six normal subject volunteers were studied
off TC and on TC once steady-state concentrations were achieved after at
least three weeks of dosing. Despite the administration of supraphysiologic
TC doses an increase in aggressive driving behavior was not detected. Likewise,
corresponding psychometric testing using the Buss-Durkee Hostility Inventory
to assess aggression was unable to detect any change in aggression in the
test subjects. Aggressive driving behavior may be increased by testosterone
administration as reported by others, but according to the authors, the
drug itself may not be responsible for these effects. Since altered driving
behavior may be multifactorial in nature, supraphysiologic doses greater
than 500 mg/wk and a semi-controlled research environment may be necessary
to produce these effects. Ellingwood V.L., Perry P.J., Yates W.R., MacInode
W.R., Watson G., Arndt S., and Holman T.L., American Journal of Drug and
Alcohol Abuse, In Press.

Evidence for a Sex-Specific Residual Effect of Cannabis on Visuospatial
Memory
Pope and his colleagues at Harvard Medical School used a novel computerized
battery of neuropsychological tests of attention to assess residual cognitive
impairment in marijuana users. They compared 25 college students who were
heavy marijuana smokers (who had smoked a median of 29 days in the last
30 days) with 30 students who were light smokers (who had smoked a median
of 1 day in the last 30 days). All subjects were tested after a supervised
period of abstinence from marijuana and other drugs lasting at least 19
hours. Although there were no significant differences between the overall
heavy and light smokers on the four subtests of attention, marked and significant
differences were found between heavy- and light-smoking women on the subtest
examining visuospatial memory. On this test, subjects were required to examine
a 6x6 "checkerboard" of squares in which certain squares were
shaded. The shaded squares were then erased and the subject was required
to indicate with the mouse which squares had formerly been shaded. Increasing
numbers of shaded squares were presented at each trial. The heavy-smoking
women remembered significantly fewer squares on this test, and they made
significantly more errors than light-smoking women. These differences persisted
despite different methods of analysis and consideration of possible confounding
variables. The authors suggest that it may be important to study the residual
effects of marijuana on men and women separately, particularly since women
have been greatly under-represented in previous studies in this area. Pope,
H.G. Jr., Jacobs, A., Mialet, J.P., Yurgelun-Todd, D., and Gruber, S. Psychotherapy
and Psychosomatics, In Press.

Abnormal Cerebral Metabolism in Polydrug Abusers During Early Withdrawal:
a 31P MR Spectroscopy Study
Mendelson and his colleagues (Harvard Medical School) performed phosphorus
magnetic resonance spectroscopy (31P MRS) at 1.5 T on nine polysubstance
abusing men. All nine patients met DSM-III-R criteria for concurrent cocaine
and heroin dependence, were neurologically normal, were negative for the
human immunodeficiency virus, and had normal clinical brain MRI scans. Patients
were scanned 2-7 days after admission to a drug treatment unit. Eleven age-matched
control subjects also were studied. The ISIS localized phosphorus spectra
were obtained from a 5-cm thick axial brain slice and a 100-cc white matter
volume. In the brain slice, the phosphorus metabolite signal expressed as
a percentage of total phosphorus signal was 15% higher for phosphomonoesters,
10% lower for nucleotide triphosphates (beta-NTP), and 7% lower for total
nucleotide phosphates in polydrug abusers compared with those in controls.
Phosphodiesters, inorganic phosphate, phosphocreatine, total phosphorus,
pH, and free magnesium concentration were unchanged. None of these parameters
correlated with the methadone dose or the number of days abstinence. Single
photon emission computed tomographic imaging of a subgroup of the patients
revealed abnormal cerebral perfusion in 80% of the patients scanned. These
data suggest that cerebral high energy phosphate and phospholipid metabolite
changes result from long term drug abuse and/or withdrawal and that these
changes can be detected and studied by 31P MRS. Christensen, J.D., Kaufman,
M.J., Levin, J.M., Mendelson, J.H., Holman, B.L., Cohen, B.M., and Renshaw,
P.F., Magnetic Resonance Medicine, 35(5): pp. 658-663, May 1996.

Problem-Service "Matching" in Addiction Treatment
McLellan his colleagues have conducted a study to identify specific patient
problems and to match professional services to those problems in four drug
abuse treatment programs. Ninety-four new patients from an Employee Assistance
Program entered treatment and were randomly assigned to either: Standard
Treatment - patients were treated in the usual manner; or Matched Services
- patients received at least three professional sessions directed at their
significant employment, family, or psychiatric problems. Matched patients
stayed in treatment longer, were more likely to complete treatment, and
had better post treatment outcomes than patients receiving treatment as
usual in these programs. The strategy of matching appropriate services to
patients' specific treatment problems was clinically and administratively
practical, attractive to patients, and responsible for a 20-30% increase
in effectiveness. McLellan, A.T., Grissom, G.R., Zanis, D., Randall, M.,
Brill, P., and O'Brien, C.P. Problem-Service "Matching" In Addiction
Treatment: A Prospective Study in Four Programs, Arch. Gen Psychiatry, In
Press.

Risk Reduction Approach for Discharged Methadone Patients
In a study of discharged methadone patients, Zanis, McLellan, Alterman,
and Cnaan randomly assigned methadone patients discharged 1 year earlier
to either a standard referral condition (n=14) or an enhanced outreach counseling
intervention (n=27) to determine if these high-risk patients could be re-engaged
into treatment. Two weeks following the intervention, 17 (63%) of the patients
assigned to the enhanced outreach condition and 1 (7%) of the patients in
the standard condition had reenrolled in treatment. The authors conclude
that this strategy may be an effective risk reduction approach for discharged
methadone patients. It may also have further implications for outreach efforts.
Zanis, D.A., McLellan, A.T., Alterman, A.I., & Cnaan, R.A. American
Journal of Psychiatry, 153: pp. 1095-1096, 1996.

Effect of Maternal Substance Abuse on the Cost of Neonatal Care
Norton and his colleagues recently reported on a study of the effects of
maternal substance abuse on the costs to neonatal care in 54 Maryland hospitals
in 1991. Investigators controlled for individual hospital effects and correlated
observations within hospitals. The findings suggest that exposure to drugs
in newborns resulted in significantly higher total hospital charges at almost
double those of non-exposed newborns (p <.01). The results demonstrated
a consistent pattern of effects on charges, mortality, and resource use
in the hospital of drug-exposed newborns due, in part, to longer lengths
of stay and higher intensity care per day. Exposure to alcohol was found
to be much less significant. The investigators suggest that their results
confirm the policy concern that maternal substance abuse has severe consequences
for the baby's health and that these cost are often borne by others. Norton,
E.C., Zarkin, G.A., Calingaert, B. & Bradley, C.J. The Effect of Maternal
Substance Abuse on the Cost of Neonatal Care, Inquiry, 33: pp. 247-257,
1996.